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Neuropeptide Regulation of Ion Channels and Food Intake
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
In both POMC and AgRP neurons, KATP channels are modulated by ATP as well as leptin and insulin. Insulin activates KATP channels on AgRP neurons by stimulating the phosphoinositide 3-kinase (PI3K) signaling pathway (Qiu et al. 2014). Leptin also utilizes the PI3K pathway to hyperpolarize cells via the activation of KATP channels (Belgardt, Okamura, and Bruning 2009). In orexin neurons, leptin electrically silences the cell via indirect activation of KATP channels (Goforth et al. 2014). In addition to receptors for peripherally secreted peptides, some neuropeptide receptors are also coupled to KATP channels for the modulation of neuronal activity in the nervous system. In the arcuate nucleus of the hypothalamus, GLP-1 receptor activation by the selective agonist liraglutide inhibits NPY neurons through activation of protein kinase A (PKA)-dependent KATP channels (He et al. 2019). In the dorsal motor nucleus of the vagus, activation of MC4R by agonist MTII and THIQ hyperpolarizes cholinergic neurons through activating KATP channels (Sohn et al. 2013). Also, KATP channels are required for GLP-1 modulation of peripheral cells (Light et al. 2002; Aizawa et al. 1998).
Asymmetric Reduction of C=N Bonds by Imine Reductases and Reductive Aminases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Matthias Höhne, Philipp Matzel, Martin Gand
Besides the identification of IREDs suitable for biocatalysis from natural resources, several protein engineering studies provided interesting enzymes useful for imine reduction and reductive amination. A few examples are listed below: The anchoring of Ir- and Ru metals via biotinylated pianostool ligands in the chiral environment of different streptavidin variants created artificial metallo enzymes with (R)- or (S)-selectivity for the production of the THIQ salsolidine (Dürrenberger et al., 2011). Formate is the hydrogen source in the catalyzed asymmetric transfer hydrogenation reactions. Further engineering studies of these hybrid catalysts are reviewed in Schrittwieser et al. (2015) and Schwizer et al. (2018).Starting with the opine dehydrogenase from Arthrobacter sp. 1C, extensive protein engineering changed the substrate spectrum to yield a reductive aminase variant for the synthesis of a tertiary amine, the antiarrhythmic drug vernakalant (Fig. 14.1). A variant carrying 29 substitutions was able to generate vernakalant with 80% de with complete conversion, if the amine is employed in 32-fold excess (Haibin et al., 2013; Schrittwieser et al., 2015).Substitution of six amino acids in the 2′-phosphate binding pocket inverted the cofactor specificity of the IRED from Myxococcus stipitatus from NADPH to NADH (Borlinghaus and Nestl, 2018).
Drug Discovery: From Hits to Clinical Candidates
Published in Divya Vohora, The Third Histamine Receptor, 2008
Sylvain Celanire, Florence Lebon, Holger Stark
From the same group, another class of compound within the aminopropoxyquinoline series has been recently reported [178]. Starting from tetrahydroisoquinoline (THiQ) scaffold 141, identified following medium-throughput screening campaign, and displaying nanomolar antagonism potency (hH3 pKi 8.6), a selected diversity of lipophilic (e.g., ethyl and cyclohexylmethyl) or polar (e.g., thiophenoyl and phenylsulfonyl) residues onto the nitrogen atom were investigated around the THiQ and the tetrahydroquinoline (THQ) analogs (Figure 5.19). The 6- and 7-substituted THiQs (142 and 143, respectively) were generally more potent than their 5- and 8-substituted THQ regioisomers, with a more pronounced subnanomolar affinity for the di-basic one (e.g., 142a, hH3 pKi 9.3; 143a, hH3 pKi 9.3). With the exception of THiQ 143b (hH3 pKi 9.5), the introduction of a phenylsulfonyl group onto all nitrogen-regioisomers led to 10-fold less potent compounds. Further derivatization of the central core was explored, and particularly, the access to the benzoazepane ring system, as exemplified by selected compound 144a ,b, displaying high potency (e.g., 144b, hH3 pKi 9.7; rH3 pKi 8.9) [179]. The introduction of polar groups (acyl, methylsulfonyl) led to monobasic compounds with weaker affinity (~1-log unit decrease) at the rH3R than at the hH3R. Compounds 143a and 144b were further profiled, displaying nanomolar hH3R inverse agonism potency in a GTPγS-binding assay (143a pIC50 9.0; 144b pIC50 8.8) as well as more than 1500-fold selectivity versus the other histamine receptor subtypes. Both compounds had good oral brain penetration as observed in a rat ex vivo binding assay, with an IC50 of 1.1 and 5.3 mg/kg for compounds 143a and 144b, respectively. Moreover, both compounds showed adequate pharmacokinetic properties in rat (>69% oral bioavailability). In a patent application, indoline 145 was also claimed as a potent H3 antagonist (pKi 9.3) [180], demonstrating that the benzo-fused cyclic amine represented an attractive scaffold that both Lilly and GSK have successfully explored. Another distinct chemical class has also been claimed by the same group around the aminoalkyloxazolyl phenyl derivatives, as exemplified by compound 146 with potent H3 antagonism properties (hH3 pKi 7.8).
1,2,3,4-Tetrahydroisoquinoline (THIQ) as privileged scaffold for anticancer de novo drug design
Published in Expert Opinion on Drug Discovery, 2021
Banoth Karan Kumar, Kondapalli Venkata Gowri Chandra Sekhar, Subhash Chander, Selvaraj Kunjiappan, Sankaranarayanan Murugesan
THIQ is a versatile scaffold that is present in numerous drug molecules and has also been reported to possess a plethora of pharmacological properties. The simple synthetic route to generate the core scaffold combined with the nucleophilicity of the secondary nitrogen makes it easier to hybridize with other versatile scaffolds of interest, making THIQ a vital scaffold for drug design. However, the anticancer potential of THIQ analogs continues to be an enigma. The information amassed in this review aims to shed light on the anticancer potential of THIQ analogs. THIQs possess enormous potential as anticancer agents. These analogs exhibit their anticancer property by inhibiting epigenetic enzymes like PRMT5 and HDACs, anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, receptors such as ER and AR as well as key targets of estrogen metabolism- aromatase and STS. Apart from being anticancer agents themselves, they have also been demonstrated to aid existing anticancer drugs by reversing their resistance via inhibiting the functions of MDR transporter P-gp. Several P-gp inhibitors such as tariquidar and elacridar have been evaluated clinically, demonstrating the ability of THIQs to act as combination therapy with existing drugs. The most promising THIQ analogs for each target described in this review are summarized in Table 1. Privileged scaffolds, as coined by Evans et al., denote molecular fragments that can bind to multiple receptors with high affinity [144,145]. THIQs have been reported to bind to multiple targets to exhibit their pharmacological properties [146]. As described in the present review, THIQs also possess a high affinity toward multiple cancer targets with good in vitro or in vivo anticancer activity. Hence, THIQs can be regarded as a ‘privileged scaffold’ and will continue to be a ‘vital scaffold’ in the field of medicinal chemistry for the development of potent and safe novel anticancer agents.